Malawi’s capital city, Lilongwe, is a poor African city of 1.5 million people where life’s basic necessities are poignantly rare. I traveled there from Chapel Hill last summer because our two communities are inextricably bound by tragedy and also by a growing sense of hope. It’s a connection that may at long last enable us to conquer the deadliest plague of our lifetimes: AIDS.
The sense of optimism comes from the triumphs of these two communities of scientists and sufferers. In 2011, after more than a decade of rigorous trials in Malawi and eight other countries, a team led by UNC infectious diseases researcher Myron Cohen discovered that the antiretroviral drugs used to treat people with HIV would also significantly reduce their ability to pass the disease on to others.
Photo by Jason Smith
Myron Cohen
It wasn’t just that finding, but the sheer magnitude of the results that surprised Cohen and the many colleagues who were integral to the work. The antiretroviral therapies reduced transmission by a near-perfect 96 percent. The journal Science honored the study as its 2011 Breakthrough of the Year.
It was a breakthrough decades in the making, one that could not have been achieved without significant investment and the dedication of people from UNC and around the world. How it happened is a lesson in big science—a lesson we should not ignore if we want to win the battles against the most formidable diseases.
Like all viruses, HIV-1 cannot replicate itself, or even exist outside cells—particularly human cells. It is almost delicate outside the human body. Once it enters the bloodstream, however, it becomes a monster, adept at ravaging its surroundings when it has the advantage and lying in almost invisible wait when under attack.
HIV-1 is comprised of nine genes and is a master of disguise. These genes enable HIV-1 to become incorporated as DNA in normal cells, indistinguishable to the cell from its own DNA. Once entrenched and active, HIV-1 hijacks the infected cells’ normal physiologic function and converts the cell into a HIV-1 producing factory. The result is the biological equivalent of a suicide machine, as infected cells churn out thousands of copies of HIV-1 until, spent of all energy, they die—or, at the very least, become ineffective in their normal roles.
Compounding the problem, HIV-1 preferentially infects immune cells, called helper T cells (or CD4+ T cells). This leaves patients with an ever-decreasing immune response, reduced control of HIV-1 infection, and increased susceptibility to other “opportunistic” infections and cancers that are ultimately fatal.
Finally, HIV-1 has the ability to “hide” from therapies directed to kill it. When stressed, HIV-1 infected cells can enter a “latent phase” and stop making HIV-1. Cells in this latent phase do not die and can be reactivated later, making it impossible to kill all the HIV-1 in an infected person with current therapies.
Today’s best therapies combine several potent antiviral drugs into a cocktail called Highly Active Antiretroviral Therapy (HAART). Some of these drugs prevent the cell from churning out copies of HIV-1; others block a key enzyme required for HIV-1 replication. A newer class of drugs aims to prevent HIV-1 from entering T cells. Unfortunately, none can completely rid the body of HIV-1 and the infected “sleeper” cells that rapidly resume their HIV-1-driven agenda once HAART is stopped.
To tackle AIDS, dozens of Manhattan Project-like teams have been created, all working on different aspects of this redoubtable killer. Cohen’s study brought together investigators at 13 sites in nine different countries—Malawi was just one. More than 4,000 subjects participated, and the study cost more than $70 million. Like the war on cancer, the war on AIDS requires such enormous resources because of the tenacity of the enemy.
This is “big science.” It’s expensive. It takes a lot of time. But if we are ever to turn around the health of Americans and citizens of the world, the power and potential of big science cannot be ignored.
The traditional work of medical research, developing visionary hypotheses and rigorous trials to test them, is only the start. Scientists like Cohen must generate and marshal massive financial and technological resources. They also must recruit and support the talent necessary to bring groundbreaking research to fruition. Often on the same day, Cohen must act as a leader, fundraiser, logician, and an improviser who arbitrates the fierce disputes that always arise among passionate scientists.
Cohen juggles these roles deftly. At 62, he’s a disarmingly persuasive, high-energy organizer who understands, in the greatest detail, the biology of HIV, the drugs to treat AIDS, and the health policy implications of a global cure. As executive dean of the UNC School of Medicine, I have seen firsthand that he possesses a charismatic ability to make people with high expectations and unrestrained egos work together for a common goal.
Cohen’s first footsteps on his 30-year journey started a few short years after his arrival in Chapel Hill, when he found himself thrust into one of the world’s early battles with HIV.
UNC recruited Cohen in 1980 because of his expertise in how immune cells kill infecting bacteria. His focus was on sexually transmitted infections (STIs), particularly gonorrhea. Foreshadowing his later work with AIDS, he was developing methods for the then-impossible task of quantifying the total amount of an infectious organism present in an individual.
This work became the basis for Cohen’s first important discovery: that men infected with both gonorrhea and HIV had more HIV in their semen and were more likely to infect their sexual partners. This knowledge would prove to be invaluable in understanding AIDS infectivity.
In 1980, there was no AIDS in Chapel Hill or anywhere else. But UNC would soon become an early hotspot for the epidemic because of its pioneering work treating one of the disease’s first target groups, hemophiliacs, who suffer from difficult-to-control bleeding. When some of these patients developed AIDS after being given blood products tainted with the as-yet undiscovered HIV-1 virus, it became clear for the first time that AIDS was transmitted through the bloodstream, was deadly, and was impossible to eradicate.
Cohen, armed with clinical and laboratory expertise in immunology and infectious diseases, saw a disaster brewing. And once scientists figured out that AIDS was a single disease—whether acquired by a blood transfusion, sexual contact, or sharing a needle—he knew that his expertise in STI transmission could make a difference.
Initial efforts in the United States focused on how to treat and prevent AIDS at home. But here the disease was most prevalent among specific populations: gay men, intravenous drug users, and hemophiliacs. In Africa, AIDS took hold across all social strata. That’s where Cohen needed to go to really understand and learn how to fight the disease.
He came to establish a freestanding AIDS research and treatment center on the other side of the globe partly by luck. “The thing I learned from the journey,” Cohen says, “was about connections that never, not in a million years, could a rational person have envisioned would help us get there. And you sure couldn’t have made up most of this.”
For Cohen the list of serendipitous opportunities is long.
First was the guidance he received from Richard Root, an early mentor at Yale. In the summer of 1979, Root suggested that Cohen and his wife, Gail Henderson, a social scientist, to go to China. They spent a year there, meeting Chinese leaders in medicine and ethics. Ten years later, an organization called Family Health International asked him to work on a multinational AIDS-prevention project because he had that year of experience working in an underdeveloped country.
Others were brought into what became known as the AIDSCAP (AIDS Control and Prevention) Project: King Holmes, often thought of as the father of STI research in the United States, Peter Piot and Marie Laga, already renowned for their work on AIDS in Zaire, and Peter Lamptey, an African public-health specialist from Ghana. Cohen and his team were scheduled to work in Malawi, an African country with a very high AIDS prevalence and a government that was willing to embrace ideas from the AIDS and STI programs at UNC.
Cohen, in all his exuberance, knew he could not manage an operation in Africa from Chapel Hill. He found the right person for the job in Irving Hoffman, a tenacious young man Cohen had once considered a nuisance. Hoffman worked for the Durham County Health Department diagnosing and treating STIs, but he had dreams of travel and making a difference. Hoffman had been calling Cohen every few months to ask for a job, and after three years, Cohen finally said yes. “The entire Malawi program could never have happened without Irving,” Cohen says. “The guy is a logistical genius.”
By early 1995, the UNC Project-Malawi, as it would come to be known, was up and running. Years before the 2011 study, it was a small unit, adjacent to a hospital. The goal then was to study HIV-1 transmission as an approach to developing preventive strategies, but the clinic treated all manner of STIs as well as other health problems. Later, Cohen’s team spearheaded efforts to build wells to bring fresh drinking water to the area.
In Malawi, Cohen, Hoffman, and their colleagues explored the connection between STIs and HIV prevention. Their initial study proved that treating gonorrhea in HIV-infected individuals markedly reduced the HIV concentration in genital secretions.
Studies at the UNC Project-Malawi dovetailed with findings by other investigators by Uganda’s Makerere University and Johns Hopkins University. This work led to a new hypothesis. “We came to believe that if we could reduce HIV concentrations in semen using potent antiretroviral drugs, we could reduce HIV transmission,” recounts Cohen. A critical component of this hypothesis was how HIV-1 in semen actually resulted in transmission. Cohen’s theory was that HIV-1 in semen must be able to enter the bloodstream through large (or even micro) breaks in the vaginal mucosa (the lining of the vaginal walls).
To test his hypothesis, Cohen the researcher had to become Cohen the recruiter. First, he recruited a visiting scientist who happened to be at UNC, Pietro Vernazza, to measure HIV in semen—only Vernazza didn’t know how to do that, so Cohen found another researcher, Susan Fiscus, to train him. Next he recruited Angela Kashuba, a talented UNC pharmacologist who was measuring concentrations of various antiretroviral drugs in blood and seminal plasma. Her technique used mass spectroscopy equipment UNC didn’t have, so they convinced nearby Glaxo Laboratories to let them use its instrument at night and on weekends.
Meanwhile, Hoffman had the clinic in Malawi running smoothly. In the three years since he’d arrived, he had trained a number of Malawians, including a lab tech, Topia Banda; a young clinic aid, Michael Chizombe; and several Malawian physicians and clinical officers. All had friends and relatives who had succumbed to AIDS.
No one made more of an impression in this regard than George Joaki. Born in Malawi, Joaki had attended medical school there, traveled to Chapel Hill for a fellowship, and then returned to Malawi to help establish a laboratory that served both the UNC Project and the local hospital, Kamuzu Central. But then Joaki lost his wife to AIDS and tested HIV-1 positive himself. Instead of returning to his home village, he redoubled his efforts to treat and prevent AIDS.
After directing the lab for five years, Joaki died on October 18, 2007. The UNC Project in Malawi raised funds for and opened the George Joaki Centre in Lilongwe, a wonderful children’s clinic dedicated to George’s contributions toward the health of all Malawians and to his courage.
As they struggled with the emotional toll of AIDS, members of the UNC-Malawi project faced staggering logistical hurdles. The specialized equipment needed to analyze the samples wasn’t available in Malawi. This meant freezing specimens and transporting them by plane back to Chapel Hill. “This was pre-9/11”, says Hoffman, “with far fewer regulations about transporting samples. We could never do that study today.”
And health care in Malawi was, and remains, a bare-bones operation. The UNC Project-Malawi partners with Kamuzu Central Hospital, a large tertiary referral hospital in Lilongwe. In the late 1990s, Kamuzu Central had 1,000 steel-frame beds but often housed significantly more patients. Nursing stations are a crowded mess of hospital charts stacked high, busy doctors and nurses, and students. There are very few specialists—a handful of pediatricians, obstetricians, surgeons, and internists—to serve millions of Malawians. The only infectious disease experts are from UNC.
Nonetheless, the team persevered. In 2001, it achieved its second breakthrough in Malawi, demonstrating that if a man was treated with antiretroviral therapy, the level of HIV-1 fell in his blood serum and also in the semen. Through a series of studies, one answer leading to the next question, Cohen developed one of the most significant hypotheses in the history of AIDS research: that treatment of HIV-1 with aggressive antiretroviral therapy (HAART) would reduce transmission.
Cohen proposed working with investigators around the world to enroll 2,000 “discordant” heterosexual couples. In approximately half the couples, the male partner was HIV-1 positive and the female partner was negative; in the other half, the female partner was HIV-1 positive and the male partner negative. Half would be treated with aggressive antiretroviral therapy at a very early stage of infection—when the immune status of the infected partner was near normal. The other half of those enrolled were treated with the standard-of-care therapy, beginning antiretrovirals a short time before immune status waned to a dangerous level.
AIDS experts had a mixed response to Cohen’s hypothesis. Some said it was crazy. After all, if HAART prevented AIDS transmission, as Cohen proposed, why was AIDS still on a rampage in the United States, where HAART therapy was widely available? Others were sure it would work and thought it would be better to skip the research altogether. Cohen countered that it would be far wiser to understand how the therapy worked and identify unforeseen risks before investing billions in an unproven approach.
The scientific rationale for the study was only one small part of the challenge. Next Cohen and colleagues had to put into place teams in the countries of interest to recruit and care for study subjects. The study supported 13 sites in nine different countries, ultimately with more than 4,000 subjects. Begun with a pilot phase in 2005 and starting full enrollment in 2007, the study cost more than 70 million dollars.
The results hit the world press with acclaim in the spring of 2011 as one of the largest AIDS-prevention trials to date. The core finding—that the sexual transmission of HIV can almost be eliminated with HAART therapy—represents one of the greatest triumphs in the field in over a decade. For the investigators, as important as the acclaim accorded to the study was the knowledge that they had made a difference for thousands of HIV-infected men and women. They study was proof that a simple, and now available, intervention could prevent AIDS transmission.
Now comes the hard part: implementing the results.
According a 2003 study, only about half of proven medical therapies in the United States make it into practice. Experts believe this number has not changed substantially during the last ten years. In developing countries, many proven therapies are incorporated into practice at even lower rates due in part to limited financial resources, but also to a host of social and cultural constraints.
Through the efforts of the UNC Malawi Project, the rollout of the HAART program has been more rapid than might have been expected. In 2013, it was estimated that 45 percent of Malawians in need of HAART had started therapy. But much remains to be done in Malawi, and even more across sub-Saharan Africa.
It is estimated that more than 20 million adults in sub-Saharan Africa are HIV-infected and that more than a million people have AIDS. Treatment of only 10 percent of them might reduce transmission of HIV-1 by more than a million cases a year. Over a decade, this could mean reducing AIDS deaths by millions. This, of course, will cost a great deal of money, an uncalculated figure certainly in the billions. At present, no one really wants to pay this sustained operational cost. Last year, the Global Fund to Fight AIDS, Tuberculosis and Malaria rejected Malawi’s request for more than $500 million towards treatment of HIV/AIDS.
Nevertheless, Myron Cohen’s work and the 2011 study point the way forward by illustrating the promise of big science. While this story has focused on just one of the efforts in the global battle against AIDS, it’s important to note that UNC-Malawi effort drew from the work of other talented researchers. It is a cog in a much larger machine.
By combining talented scientists with highly advanced technology and passionate, visionary leadership, the UNC-Malawi project demonstrated how massive resources can solve the world’s most complex medical mysteries. At a time of budgetary constraints, it reminds us that true breakthroughs depend on thoughtful investment.
Shortly after the study was published, then-Secretary of State Hillary Clinton stated, “The goal of an AIDS-free generation is ambitious, but it is possible.”
No one knows when, or exactly what the cure for AIDS will entail, but a cure will be found—and proven—by big science.